Pharmaceutical compounds

ABSTRACT

Compounds of formula (I) ##STR1## wherein each X separately is halogeno, hydroxy, C 1-4  alkyl, C 1-4  alkoxy, nitro or an unsubstituted or substituted amino group NRR&#39; in which R and R&#39; are each separately selected from hydrogen, C 1-4  alkyl groups and C 2-4  halogenated alkyl groups; 
     wherein Y is halogeno, hydroxy, C 1-4  alkoxy or an unsubstituted or substituted amino group NRR&#39; in which R and R&#39; are as defined above; 
     wherein n represents 0, 1, 2 or 3 and n&#39; represents 1, 2, 3 or 4; 
     wherein R 1  and R 2  each separately represent hydrogen, halogeno, phenyl or a C 1-4  alkyl group, or together represent a group ═NOR&#34; in which R&#34; is hydrogen or is a group ZC(O)-- or (ZO) 2  P(O)-- where Z is a C 1-4  alkyl group; and 
     wherein R 3  and R 4  each separately represent hydrogen, acetyl, phenyl, 2,2,2-trichloro-1-hydroxyethyl or a C 1-4  alkyl group, or together represent a group ═CHR&#34;&#39; in which R&#34;&#39; is a C 1-4  alkyl, C 1-4  halogenated alkyl or phenyl group or represent a group ═CH--CH═CHR&#34;&#39; in which R&#34;&#39; is as defined above; the compound or its physiologically acceptable salt, are of value in the treatment of depression and/or in memory enhancement.

This application was filed under 35 U.S.C. 371 and was based uponInternational Application No. PCT/IB94/00009, filed Jan. 10, 1994.

The invention relates to hydrazides of phosphorylated carboxylic acidshaving therapeutic activity, particularly in treating depression and foreffecting memory enhancement.

Razumov et al., Zhurnal obshchei khimii, 1967, vol. 37, 421-424 describehydrazides of phosphorylated carboxylic acids of structure R₁ R₂ P(O)CH₂C(O)NHNH₂ in which R₁ and R₂ are selected from phenyl, p-tolyl, ethyl,ethoxy and butoxy groups and N-substituted derivatives thereof. Thesehydrazides were reported as showing a low level of antimicrobialactivity. U.S. Pat. Nos. 4,162,264 and 4,162,311 describe a hydrazide ofdiphenylphosphinylacetic acid diphenylphosphinylacetohydrazide,hereinafter "DPAH", (C₆ H₅)₂ P(O)CH₂ C(O)NHNH₂ ! which has vegetropic,anti-epileptic and anti-serotonin properties. Hydrazides ofphosphorylated acetic acids, which display a low level of neurotropicactivity, are also described by Ismagilov et al., Khim.-Farm. Zhurnal,1982, 16, 296-300 and Zhuravleva et al., Khim.-Farm. Zhurnal, 1978, vol.12, 79-93 (both also published in English translation).

It is well known that patients who suffer from neurodegenerativediseases, for example Alzheimer's disease and Parkinson's disease, or,as a result of a stroke or head injury or merely as the result ofadvancing age, suffer from memory-loss, often also have symptoms rangingfrom mild anxiety to severe depression. Such patients respond totreatment with neuroprotective agents and in particular memory-enhancingdrugs (so-called "cognitive enhancers") and anti-depressants.

It is an object of the present invention to expand the arsenal ofremedies available for use in these areas and it has now been found, forexample, that the novel compound(2-chloroethoxy)-(p-N,N-dimethylaminophenyl)phosphinylacetohydrazideformula) (I), X═p--(CH₃)₂ N, Y═Cl, n=1, n'=2, R¹ =R² ═H and R³ ═R⁴ ═H!is a potent neuroprotective agent and in particular displaysanti-depressant and memory enhancing activity.

Accordingly the present invention comprises a compound having thefollowing general formula (I): ##STR2## wherein each X separately ishalogeno, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro or an unsubstituted orsubstituted amino group NRR' in which R and R' are each separatelyselected from hydrogen, C₁₋₄ alkyl groups and C₂₋₄ halogenated alkylgroups;

wherein Y is halogeno, hydroxy, C₁₋₄ alkoxy or an unsubstituted orsubstituted amino group NRR' in which R and R' are as defined above;

wherein n represents 0, 1, 2 or 3 and n' represents 1, 2, 3 or 4;

wherein R¹ and R² each separately represent hydrogen, halogeno, phenylor a C₁₋₄ alkyl group, or together represent a group ═NOR" in which R"is hydrogen or is a group ZC(O)-- or (ZO)₂ P(O)-- where Z is a C₁₋₄alkyl group; and

wherein R³ and R⁴ each separately represent hydrogen, acetyl, phenyl,2,2,2-trichloro-1-hydroxyethyl or a C₁₋₄ alkyl group, or togetherrepresent a group ═CHR"' in which R"' is a C₁₋₄ alkyl, C₁₋₄ halogenatedalkyl or phenyl group or represent a group ═CH--CH═CHR"' in which R"' isas defined above, with any phenyl group present in R³, R⁴ or R³ +R⁴optionally being substituted by 1 to 3 groups selected from halogeno,hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro and unsubstituted or substitutedamino groups NRR' in which R and R' are as defined above; the compoundoptionally being in the form of a physiologically acceptable salt.

In the compounds (I) halogeno groups are preferably iodo, bromo, orespecially chloro and the C₁₋₄ alkyl and alkoxy groups may comprisealkyl groups which are branched or preferably straight chain such asmethyl, ethyl, propyl, isopropyl, butyl and isobutyl, with the smallergroups such as methyl being of particular interest. Halogenated alkylgroups are constituted of such halogeno and alkyl groups, such groupspreferably containing one halogeno group and with the C₂₋₄ halogenatedalkyl groups preferably being substituted on a carbon atom other thanthe α carbon atom of the alkyl group, as for example in 2-chloroethyl.

As regards the group (X)_(n), n is preferably either 0, in which casethe phenyl group in the compound (I) is unsubstituted or, moreconveniently, n is 1. When n is other than 0, for example 1, X ispreferably halogeno or especially NRR'. Disubstituted amino NRR' groupsare preferred, for example dialkylamino groups such as dimethylamino.Although the substituent(s) X may be present at various positions of thering it is preferred that the substituent, or at least one substituentwhere more than one is present, is at the para position of the benzenering with respect to the phosphorus-containing grouping.

As regards the group Y this is preferably a halogeno group and n' isconveniently 4, 3 or especially 2 (compounds in which n' is 1 being ofless interest particularly when Y is other than halogeno) so that apreferred grouping Y(CH₂)_(n) 'O-- is 2-chloroethoxy. The groups R¹ andR² conveniently are each hydrogen although there is also interest incompounds in which each is halogeno or one is hydrogen and the other ishalogeno, phenyl or alkyl, for example methyl, as well as the groups═NOR".

As regards R³ and R⁴, R³ is preferably hydrogen or together with R⁴represents a divalent group. Examples of various specific groups NR³ R⁴have R³ ═R⁴ ═H; R³ ═H and R⁴ ═COCH₃, C₆ H₅, CH(OH)CCl₃ or especially CH₃or C₂ H₅ ; and R³ +R⁴ ═CHCH₃, CHCH₂ Cl, CHCH═CHCH₃, CHCH═CHC₆ H₅ or CHC₆H₅ as well as such groups R⁴ and R³ +R⁴ containing a benzene ring inwhich there is substitution in the benzene ring by one or more halogeno,hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro and unsubstituted or substitutedamino groups NRR', for example R⁴ being or R³ +R⁴ containing a groupwhich is 2-HOC₆ H₄, 2,4-(HO)₂ C₆ H₄, 4-CH₃ OC₆ H₄, 2,4-(CH₃ O)₂ C₆ H₃,4-(CH₃)₂ NC₆ H₄, 4-ClC₆ H₄, 2,4-Cl₂ C₆ H₃, 2-NO₂ C₆ H₄, 3-NO₂ C₆ H₄ or4-NO₂ C₆ H₄.

Examples of specific types of compound (I) are those in which NR³ R⁴ isNHCH(OH)CCl₃, N═CH--CH═CHCH₃, N═CH--CH═CHC₆ H₅, N═CH--C₆ H₄ --NO₂(meta), N═CH--C₆ H₄ --OH (ortho) or especially NH₂. In preferredcompounds (I) such a group NR³ R⁴ is combined with R¹ ═R═hydrogen, nbeing 0 or X being dimethylamino with n being 1, especially at the paraposition, and Y(CH₂)_(n) 'O being a halogenoalkoxy group, especially agroup in which n' is 2 such as 2-chloroethoxy.

The most preferred compound is2-chloroethoxy-(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide,hereinafter referred to as CAPAH and its physiologically acceptablesalts, such as the hydrochloride.

The compounds (I) in which R³ and R⁴ are each hydrogen may besynthesised through the reaction of hydrazine, usually as the hydrate,with a corresponding phosphoryl acetic acid ester. In preferred suchesters, the ester grouping --COOR₃ corresponding to the grouping--CONHNR³ R⁴ of the compound (I) contains a group R₃ which is a C₁₋₄alkyl group, for example methyl or ethyl. Such ester intermediates areconveniently obtained using the general method described by Arbuzov etal., News of the USSR Academy of Sciences, Chemical Sciences Department,1952, 854-859 and by Henning et al., J. Prakt. Chem., 1965, 29, 86-92 inwhich an ester of the corresponding phenyl phosphonous acid is reactedwith an appropriate alkyl haloacetate. Compounds (I) in which one orboth of R³ and R⁴ are not hydrogen may be prepared directly by the useof an alternative reagent to hydrazine or alternatively may be preparedby the further reaction of the compound in which R³ and R⁴ are eachhydrogen with the appropriate reagent. Thus, for example a grouping NR³R⁴ of the form NHCH(OH)CCl₃ may be produced using trichloroacetaldehydeand the groups N═CH--CH═CHCH₃ and N═CH--CH═CHC₆ H₅, for example, may beproduced using crotonaldehyde and cinnamaldehyde, respectively.

In an alternative procedure, CAPAH and its analogues in which Y(CH₂)_(n)'O is a halogeno-ethoxy group may be prepared by way of a "one potsynthesis" by reacting p-N,N-dimethylphenyldichlorophosphine withethylene oxide and subsequently treating the reaction product with ethylchloroacetate and hydrazine hydrate or another ester XCH₂ COOR in whichX is a halogeno group and R is an alkyl group, for example of 1-4 carbonatoms. This procedure, which is based on that described in U.S. Pat. No.4,162,264 for the preparation of the compound (C₆ H₅)₂ P(O)CH₂C(O)NHNH₂, effects the following reaction scheme A. ##STR3##

The initial reactant, para-N,N-dimethylaminophenyldichlorophosphine isobtained by a known method (V. V. Kormachev, S. N. Chalykh, V. P. Pavlov& V. A. Kukhtin, "Syntheses based on4-N,N-dimethylaminophenyldichlorophosphine", Fosfororganicheskiesoedineniya i polimery Organophosphorous compounds and polymers!,Collected articles, Chuvashia State University, Cheboksary, 1976,p.119).

Other procedures known to those skilled in the art of chemical synthesismay also be applied to the synthesis of the compounds of use in thepresent invention.

Firstly, compounds in which Y is a group other than a halogeno groupsuch as a disubstituted amino group may be prepared through the use ofthe procedure illustrated in the following reaction scheme B for thepreparation of the compound(2-N,N-dimethylaminoethoxy)(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide.##STR4##

In the first step four molar equivalents of diethylamine are used withthe formation in the reaction of two molar equivalents of diethylaminehydrochloride.

Secondly, compounds in which R¹ and R² together represent a group═NOHmay be prepared through the use of the procedure illustrated in thefollowing reaction scheme C for the preparation of the compound(2-chloroethoxy)(p-tolyl)phosphinyl!(hydroxyimino)-acetohydrazide.##STR5##

As indicated hereinbefore, the compounds of the invention have beenfound to have a valuable therapeutic action as anti-depressant andmemory enhancing agents.

Accordingly the invention further comprises the compounds of formula (I)as defined hereinbefore for use in therapy.

The invention also includes pharmaceutical compositions comprising as anactive component a compound of formula (I) as described hereinbeforetogether with a physiologically acceptable diluent or carrier.

As indicated, the compounds may be formulated as salts together withphysiologically acceptable inorganic or organic acids, there beingparticular interest in the salts of compounds in which R₁ ═R₂ ═hydrogen.These may, for example, be salts with the hydrohalic acids such ashydrochloric acid but when so formulated it may also be appropriate touse methane sulphonic acid, isethionic acid, tartaric acid or anothersolubilising acid.

The compounds of formula (I) may be formulated singly or as a mixture oftwo or more compounds for use in a pharmaceutical composition by avariety of methods.

The pharmaceutical composition of the invention may be in a formsuitable for oral use, for example a tablet, capsule, aqueous or oilysolution, suspension or emulsion; for nasal use, for example a snuff,nasal spray or nasal drops; for vaginal or rectal use, for example asuppository; for administration by inhalation, for example a finelydivided powder or a liquid aerosol; for sub-lingual or buccal use, forexample a tablet or capsule; or for parenteral use (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),for example a sterile aqueous or oily solution or suspension. Ingeneral, the above compositions may be prepared in a conventional mannerusing conventional excipients, using standard techniques well known tothose skilled in the art of pharmacy.

The compounds of the invention find use in the treatment of clinicaldepression, particularly reactive depression although they may also beof use in the treatment of manic depression and schizophrenia, and alsoin the treatment of memory-impaired individuals. A particular advantageof the compounds of the invention is that they combine memory enhancing,anti-depressant, anxiolytic and neuroprotective properties. Hence thepharmaceutical composition of the invention is especially useful inpatients suffering from combinations of these symptoms. Thus oneparticular area of use is as a combined memory enhancer andanti-depressive or anti-anxiety agent, particularly after ischaemia,although another area of use is simply as an anti-depressant. A furtherpotential use which may be mentioned is for correction of sedativeeffects of benzodiazepine tranquillizers and for treatment ofcomplications induced by neuroleptic drugs.

It will be appreciated that the dosage levels used may vary over a widerange depending on the activity of the particular compound used, theindividual patient who is receiving the composition and the conditionbeing treated. By way of guidance, however, it may be indicated that forany of these treatments the compounds of the invention will often beadministered at a total dose for a 70 kg human being of between 1 and1,000 mg daily, especially between 10 and 300 mg daily, although theprecise dosage will depend on the particular individual and may onoccasion fall outside this range. Where the compound is used purely asan anti-depressive, rather than with a combined memory enhancer effect,the dosages are likely to be somewhat higher in the range than for thecombined effect treatment.

The present invention thus includes a method for the treatment of apatient suffering from depression or in need of memory enhancement whichcomprises administering to said patient a therapeutically effectiveamount of a compound of formula (I) as defined hereinbefore.

Furthermore the invention includes the use of a compound of formula (I)for the manufacture of a medicament for use in treating depressionand/or for effecting memory enhancement.

The invention is illustrated by way of example only with reference tothe following drawings, in which:

FIG. 1 shows the effect of CAPAH on apomorphine-induced hypothermia inmice;

FIG. 2 shows the effect of CAPAH on apomorphine-induced stereotypy inrats;

FIG. 3 shows the effects of CAPAH on L-dopa induced hypothermia andmotor activity, and

FIG. 4 shows the effect of CAPAH on haloperiodol-induced catalepsy.

EXAMPLE 1

Synthesis of 2-chloroethoxy(phenyl)phosphinylacetohydrazide (A) Tostirred ethyl 2-chloroethoxy(phenyl)phosphinylacetate.sup.(1) (0.1 mole)was added hydrazine hydrate (0.3 mole) at room temperature. The reactionmixture was then kept at room temperature for 12-24 hours after whichtime the resultant solid was filtered off, washed with ethanol:ether(1:1 v/v) and recrystallized from ethanol to give the title compound in56% yield as white crystals of melting point 159°-160° C. Found, P11.13%, N 9.84%; Calculated for C₁₀ H₁₄ ClN₂ O₃ P: P 11.21%, N, 10.12%.δ³¹ P (dimethyl sulphoxide) 40.5 ppm.

(1) The ethyl 2-chloroethoxy(phenyl)phosphinylacetate was obtained bythe general procedure of Arbuzov et al., News of the USSR Academy ofSciences, Chemical Sciences Department, 1952, 854-859 and Henning etal., J. Prakt. Chem., 1965, 29, 86-92 which involves reaction of thecorresponding ester of the phenylphosphonous acid with an appropriatealkyl haloacetate.

(B) The procedure described under (A) may be applied, usingintermediates obtained as described in the footnote, to the preparationof various compounds of formula (I), for example the correspondingp-chloro, p-methyl and p-dimethylamino substituted compounds.

EXAMPLE 2

Synthesis of CAPAH(2-chloroethoxy)(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide!

(1) A four-necked flask fitted with a thermometer, gas intake pipe,agitator and reflux condenser was filled with 30.6 g (0.137 mole) ofp-N,N-dimethylaminophenyldichlorophosphine and 22.3 g (0.206 mole)methyl chloroacetate. After dissolving thep-N,N-dimethylaminophenyldichlorophosphine, the flask contents werecooled to 0°, and, at a temperature of 0°-100°, 12.05 g (0.274 mole) ofethylene oxide was admitted. The reaction complete, the reaction mixturewas heated to room temperature, agitated for 1/2 hour and the excessethylene oxide was removed in the vacuum of a water-jet pump. The refluxcondenser was then replaced with a Liebig condenser and the reactionmixture slowly heated and vigorously stirred. The reaction proceeded at100°-110° and was completed in three to four hours. At the end of thereaction, the temperature was raised to 120° C. and held there for 15-20minutes. The reaction mixture was then cooled to 100°, thedichloroethane and unreacted methyl chloroacetate were distilled off ina vacuum at a residual pressure of 10-15 mm Hg. To the resultant mixture₆.84 g (0.274 mole) of hydrazine hydrate was added in small portions atroom temperature, while stirring. In two hours the reaction masscrystallised. The crystals were filtered off, rinsed first in alcoholthen in ether and dried in air. Thus CAPAH was obtained (28.0 g, 63%) aswhite crystals of melting point 143°-148° C.

After recrystallisation from chloroform, 24.6 g (55%) of pure CAPAH wasobtained of melting point 155°-156° C. Found: P 9.20, 9.31%; N 13.50,13.31%. Calculated for C₁₂ H₁₉ ClN₃ O₃ P: P 9.70%, N 13.14%. ν_(max)(KBr disc) 1197 (P═O), 1650 (NH), 1695 (C═O), 3220-3315 (NH) cm⁻¹. δ³¹P(dimethyl sulphoxide) 40.0 ppm.

(2) In a first variant of the procedure described under (1) thep-N,N-dimethylaminophenyldichlorophosphine is replaced by an equimolaramount of p-chlorophenyldichlorophosphine or p-tolyldichlorophosphine toprovide (2-chloroethoxy)(p-chlorophenyl)-phosphinylacetohydrazide or(2-chloroethoxy)(p-tolyl)phosphinylacetohydrazide.

(3) In a second variant of the procedure described under (1) thehydrazine is replaced by an equimolar amount of phenylhydrazine toprovide N.sup.β-(phenyl)-(2-chloroethoxy)(p-N,N-dimethylaminophenyl)-phosphinylacetohydrazide.

EXAMPLE 3

Synthesis of CAPAH Hydrochloride

To a solution of 0.005 mole of CAPAH in 10 ml of ethanol was added anequivalent of hydrogen chloride dissolved in ethanol (8% w/v). Theethanol was removed under vacuum at room temperature and the resultingoil was crystallised. The crystals were filtered from the residualliquid and washed with ether to provide CAPAH hydrochloride in 86% yieldas white crystals of m.p. 171° C. having a high water solubility. Found:P 8.75, 8.85%; N 11.50, 11.75%; Cl 19.99, 20.34%. Calculated for C₁₂ H₂₀Cl₂ N₃ O₃ P: P 8.72%; N 11.78%; Cl 19.94%. δ³¹ P (H₂ O) 33.8 ppm.

EXAMPLE 4

Synthesis of N.sup.β-(2,2,2-trichloro-1-hydroxy)-(2-chloroethoxy)(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide

To a suspension of 0.005 mole of CAPAH in 5 ml of dry chloroform at roomtemperature 0.007 mole of trichloroacetaldehyde was added in portionswith stirring. The temperature of the reaction mixture increased to 35°C. by the end of the reaction. On completion of the reaction thereaction mixture was stirred at room temperature for 3 hours and thesolvent was then removed under vacuum. The resultant oil was purified byseveral precipitations from hexane to provide the title compound in 52%yield as pale yellow crystals of melting point 115°-116° C. Found: P₆.25, 6.35 %; N 8.80, 8.62%. Calculated for C₁₄ H₂₀ Cl₄ N₃ O₄ P: P ₆.66%; N 9.00%. δ³¹ P (dimethyl sulphoxide) 36.7 ppm.

EXAMPLE 5

Synthesis of N.sup.β-(but-2-enylidene)-(2-chloroethoxy)-(p-N,N-dimethylaminophenyl)phosphinylacetohydrazideand related compounds

(A) To a suspension of 0.005 mole of CAPAH in 5 ml of dry chloroform atroom temperature was added 0.007 mole of crotonaldehyde in 2 ml ofchloroform in portions with stirring. As the reaction proceeded thetemperature of the reaction mixture increased to 26°-30° C. until theCAPAH was completely dissolved. The reaction mixture was maintained atroom temperature for 6 to 12 hours and the solvent was then removedunder vacuum. The resulting oil was purified by several reprecipitationsfrom hexane to provide the title compound as a yellow powder in 67%yield of melting point 145°-146° C. Found: P 8.20%; N 11.57%. Calculatedfort C₁₆ H₂₄ ClN₃ O₃ P: P 8.36%; N 11.30%. δ³¹ P (dimethyl sulphoxide)37.5, 38.5 ppm.

The compound was poorly soluble in most organic solvents and in waterbut soluble in dimethyl sulphoxide and other aprotic polar solvents. Thetwo ³¹ P n.m.r. signals indicate the presence of syn and anti isomericforms.

(B) The procedure described under (A) above was repeated usingcinnamaldehyde, m-nitrobenzaldehyde or salicylaldehyde in place ofcrotonaldehyde to produce the N.sup.β -cinnamaylidene, N.sup.β-m-nitrobenzylidene and N.sup.β -o-hydroxybenzylidene compounds with theproperties indicated in Table 1 below. The solubility of these compoundsis similar to that of the compound described under (A).

                                      TABLE 1                                     __________________________________________________________________________              Yield                                                                            Melting Point                                                                        Found %                                                                             Calculated %                                                                        δ.sup.31p                               N.sup.β Substituent                                                                %  °C.                                                                           P  N  P  N  (CH.sub.3).sub.2 SO                           __________________________________________________________________________    C.sub.6 H.sub.5 CH═CH--CH═                                                      83 118-120                                                                              6.97                                                                             9.60                                                                             7.14                                                                             9.67                                                                             37.1,38.0                                     m-NO.sub.2 C.sub.6 H.sub.4 CH═                                                      81 146-147                                                                              7.00                                                                             12.47                                                                            6.85                                                                             12.38                                                                            35.3,36.4                                     o-HOC.sub.6 H.sub.4 CH═                                                             95 198-200                                                                              7.22                                                                             10.05                                                                            7.33                                                                             9.91                                                                             36.1,37.5                                     __________________________________________________________________________

EXAMPLE 6

Synthesis of(2-N,N-dimethylaminoethoxy)-(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide

The reaction scheme B described hereinbefore is used to synthesise thiscompound starting from p-N,N-dimethylaminophenyldichlorophosphine.

EXAMPLE 7

Synthesis of(2-chloroethoxy)(p-tolyl)phosphinyl!(hydroxyimino)acetohydrazide

The reaction scheme C described hereinbefore is used to synthesise thiscompound starting from p-chlorophenyldichlorophosphine and ethyleneoxide.

EXAMPLE 8

Toxicity of CAPAH

It was established in the course of pharmacological investigation that2-chloroethoxy(p-N,N-dimethylaminophenyl)-phosphinylacetohydrazide(CAPAH) is a biologically active substance which selectively affects thecentral nervous system. A comparison of the proposed compound with itsnearest analogue in structure and purpose,diphenylphosphinylacetohydrazide (DPAH), has shown that CAPAH is a lesstoxic compound with a significantly greater interval between the maximumtolerance dose ("MTD") and the LD₁₀₀ than DPAH (Table 2).

                  TABLE 2                                                         ______________________________________                                        Compound LD.sub.100 (mg/kg)                                                                        LD.sub.50 (mg/kg)                                                                         MTD (mg/kg)                                  ______________________________________                                        CAPAH    1200        960 ± 35.0                                                                             700                                          DPAH      500        315 ± 24.8                                                                             200                                          ______________________________________                                    

EXAMPLE 9

Impact of CAPAH on Dopaminergic Activity

(1) Interaction with apomorphine.

The effect of CAPAH on apomorphine-induced hypothermia and stereotypywas evaluated. The hypothermia was induced by subcutaneously injectingmice with 25 mg/kg of apomorphine. The change in skin temperature wasrecorded by a TPEM-1 thermometer immediately before injecting withapomorphine and also 60 and 120 minutes after the administration.

Stereotypy in rats was induced by subcutaneous administration of 20mg/kg of apomorphine. The total duration of the stereotypy episode wasevaluated and also the intensity of individual components thereof(licking, gnawing, sniffing). CAPAH was administered 40 minutes beforethe apomorphine as a 90 mg/kg dose to the mice and 100 mg/kg dose to therats. The results show no effect of CAPAH on apomorphine-induced effects(FIGS. 1 and 2).

(2) Interaction with L-dopa.

L-3,4-dihydroxyphenylalanine (L-dopa) was administered in a 150 mg/kgdose, which induces hypothermia, depression and reduction of motoractivity. CAPAH administered in a dose of 100 mg/kg to mice showed noactivity (FIG. 3).

(3) Impact on catalepsy caused by haloperidol.

Haloperidol in a vial was administered subcutaneously in a 5 mg/kg dose40 minutes after the CAPAH (90 mg/kg).

Catalepsy was evaluated from the animal's ability to maintain an awkwardposture (hind legs placed on a 30 mm high pedestal and forelegs on thebench) for 90 seconds at intervals of 10, 60 and 120 minutes after thelatest administration of haloperidol.

The results are shown in FIG. 4.

EXAMPLE 10

Memory Enhancing Activity of CAPAH

The protective effect of the compound CAPAH was studied in relation toboth scopolamine and hypoxia induced amnesia in gerbils by the passiveavoidance test.

METHODS

Training Procedure

Gerbils underwent a training schedule of "passive avoidance", i.e. theylearned not to enter a dark compartment into which an electric shock wasdelivered.

Scopolamine Induced Amnesia

Gerbils received an intra-peritoneal injection of scopolamine (0.5mg/kg) 30 minutes before the training procedure. The ability of CAPAH,given prior to scopolamine, to prevent the induced amnesia wasdetermined.

Hypoxia Induced Amnesia

The gerbils were trained as described above. To produce a hypoxicenvironment a gas-mixture (4% oxygen, 96% nitrogen) was blown through aplastic box (12 l/min). Immediately after the training period the gerbilwas put into this hypoxic environment and removed when gasping was shown(maximum stay in the hypoxic box is 40 seconds).

Passive Avoidance Test

The gerbils were trained as described above in a step-down type passiveavoidance apparatus (Model E13-08, Coulbourn Instruments, Lehigh Valley,USA), divided into a safe part and a grill part. The experimentalchamber (16×16×20 cm) had a safety platform (6×16×3 cm) and a floor madeof stainless steel rods. Training of the passive avoidance was carriedout for 5 minutes. The gerbils were placed on the safety platform andreceived a series of mild electric shocks, 0.12-0.2 nA (shocksensitivity determined for each batch of gerbils) for 3 seconds every ₆seconds when it stepped off the grill. Gerbils were returned to theapparatus for testing 24 hours later and their step-down latencies tothe grill floor (recall latency) were recorded (maximum 60 seconds).Control animals had a high step-down latency.

In both these series of experiments Piracetam was used as a control.

RESULTS

The results are shown in Tables 3 and 4 below.

                  TABLE 3                                                         ______________________________________                                        Effects of CAPAH on hypoxia induced amnesia in the                            Mongolian Gerbil.                                                                                      Latency                                              Groups             n     (sec ± SEM)                                       ______________________________________                                        Control            13    131 ± 16                                          Hypoxia            11     69 ± 17*                                         Piracetam (100 mg/kg)                                                                            10    107 ± 19                                          CAPAH                                                                          1 mg/kg            9     135 ± 21**                                        10 mg/kg          10    111 ± 25                                           30 mg/kg           9     71 ± 28*                                         100 mg/kg          10    119 ± 23                                          300 mg/kg           5    20 ± 8*                                           ______________________________________                                         Statistical Analysis: ANOVA followed by Dunnett ttest                         *Significantly different from Control (p < 0.05)                              **Significantly different from Hypoxia (p < 0.05)                        

In this test CAPAH is active in doses 1, 10, 100 mg/kg. Activity wasabsent in doses 30, 300 mg/kg. The dose of 300 mg/kg (1/3 DL50) istoxic. Probably, the mechanism of CAPAH positive effect in doses of 1,10, 100 mg/kg is different. In the dose of 100 mg/kg CAPAH revealsdopamine-mimetic activity. This dose of the compound reduces haloperidolinduced catalepsy (5 mg/kg--hypodermic injection).

CAPAH activity in small doses (1 and 10 mg/kg) may be caused by someother mechanism, for example a membrane related effect which mayanticipate an intervention into metabolic processes on the cellularlevel.

                  TABLE 4                                                         ______________________________________                                        Effect of CAPAH on scopolamine induced amnesia in the                         Mongolian Gerbil.                                                                                      Latency                                              Groups             n     (sec ± SEM)                                       ______________________________________                                        Control            13    117 ± 18                                          Scopolamine (0.5 mg/kg)                                                                          14    18 ± 6*                                           Piracetam (100 mg/kg)                                                                            10    73 ± 24                                           CAPAH                                                                          1 mg/kg           10    35 ± 17*                                           10 mg/kg          10    52 ± 21*                                           30 mg/kg          10    36 ± 17*                                          100 mg/kg          10    49 ± 16*                                          300 mg/kg           8    76 ± 30                                           ______________________________________                                         Statistical Analysis: ANOVA followed by Dunnett ttest                         *Significantly different from Control (p < 0.05)                         

Statistically significant reversal of scopolamine-induced amnesia wasobserved only at 300 mg/kg, although a trend towards memory enhancementwas observed at the lower doses.

EXAMPLE 11

Anti-depressive Activity of CAPAH

To illustrate the anti-depressant activity of CAPAH, "behaviouraldespair" and "learned helplessness" models were used.

(A) Behavioural Despair Model

In this test, mice (tetrahybrids SVA) were obliged to swim in a limitedspace, presented as a cylindrical vessel which was 15 cm high containinga water level of ₆ cm maintained at a temperature of 21° C. A "slowingdown" of swimming activity was observed. This "slowing down" is regardedto reflect the state of lowering of spirits and increasing despair ofthe mice. The slowing down is diminished by anti-depressants.

CAPAH was investigated in acute and chronic application (for 10 days).The mean duration of animal immobility for 6 minutes of observation wasestimated in seconds.

CAPAH was injected in a dose of 90 mg/kg 40 minutes before theexperiment. The results of the experiment indicated that the repeatedapplication of CAPAH lessens the duration of "slowing down" which issuggestive of anti-depressant activity.

The results are shown in Table 5 below.

                  TABLE 5                                                         ______________________________________                                        CAPAH Influence on the Duration of Mice Immobilization                        According to "Behavioural Despair" Test                                                Single Injection                                                                        Repeated Injection                                         ______________________________________                                        Control    225 ± 12.5 min.                                                                        225.0 ± 12.5                                        CAPAH      210 ± 22.5 min.                                                                        177.5 ± 17.5*                                       ______________________________________                                         *Significantly different from control (p < 0.05)                         

(B) Learned Helplessness Model

The phenomenon of learned helplessness is that exposure touncontrollable stress produces deficits in subsequent learning tasks.The preliminary non-avoidable aversive phase of the test was carried outin dark chambers (30 cm×15 cm×15 cm) with electrodes in the floor. Micewere placed into the chambers individually where they received a numberof stimuli (150 mkA, 60 Hz) for 6 seconds with 30 second intervals.Exposure lasted for 40 minutes. 24 hours later the animals were testedin a "shuttle" chamber which consisted of two compartments with theelectrode floor connected by the opening situated 1 cm above the base.The entrance to the neighbouring compartment was blocked by a dooroperated automatically. Stimulation (150 mkA) was directed in turn toeach compartment with 30 second intervals and 4 seconds lag. After 10sessions the door was closed and electric current stopped. The averagesummary latent time of avoidance was estimated as well as the totalnumber of non-fulfilled reactions.

Experiments were carried out in 40 male rats weighing 18-20 g.Melipramine was used as a standard preparation. Preparations wereinjected intraperitoneally in doses: CAPAH--90 mg/kg, melipramine--7mg/kg. Control animals received an equal quantity of distilled water. Inthe first control group (control 1) mice were not exposed tonon-avoidable aversive stimulations; in the second control group(control 2) the animals were exposed to the preliminary non-avoidableaversive influence but without drug preparations. During the nexttesting (in 24 hours) in a "shuttle chamber" the animals preliminaryplaced in the situation of non-avoidable stress displayed a realbehaviour deficit preserved on repeated testing on the ₆ th and 12thdays.

CAPAH (90 mg/kg) demonstrated marked anti-depressant effects, both aftersingle and chronic treatment as shown in Table 6 hereinafter.

                                      TABLE 6                                     __________________________________________________________________________    CAPAH Influence on Indices of "Avoidance Reaction"                            in Mice Subjected to Preliminary Nonavoidable                                 Stress-Influence on "Learned Helplessness" Model                                        Percent of                                                                           Average                                                                             Percent of                                                                           Average                                                                             Percent of                                                                           Average                                  Dose                                                                              nonavoidance                                                                         latence of                                                                          nonavoidance                                                                         latence of                                                                          nonavoidance                                                                         latence of                               in  from total                                                                           avoidable                                                                           from total                                                                           avoidance                                                                           from total                                                                           avoidable                          Substances                                                                          mg/kg                                                                             test number                                                                          period                                                                              test number                                                                          period                                                                              test number                                                                          period                             __________________________________________________________________________              single injection                                                                           6-fold injection                                                                           12-fold injection                         Control 1 17%    10.1 ± 1.3                                                                       16%     9.5 ± 0.9                                                                        17%    8.8 ± 1.0                      Control 2 63%.sup.x                                                                            16.1 ± 1.6.sup.x                                                                 54%.sup.x                                                                            15.4 ± 1.7.sup.x                                                                  56%.sup.x                                                                           15.2 ± 1.5.sup.x                CAPAH 90  19**   12.1 ± 1.5                                                                        2%**   9.0 ± 0.7**                                                                     1.3%**  7.9 ± 0.7**                    Melipramine                                                                          7  43%    13.5 ± 1.8                                                                       29%    11.8 ± 1.5                                                                        11%*   9.2 ± 1.1*                     __________________________________________________________________________     .sup.x = p < 0.05; .sup.xx = p < 0.01 concerning control 1 (unstressed        mice)                                                                         * = p < 0.05; ** = p < 0.01 concerning control 2 (stressed mice)         

EXAMPLE 12

Neuroprotective Activity of CAPAH

The potential of CAPAH to provide neuroprotection following a stroke wasillustrated by its anti-hypoxic properties in mice using both hypoxiainduced directly by lack of oxygen in the atmosphere and hypoxia inducedby sodium nitrite injection.

(A)

White mice in groups of six with a standard weight of 18 grams wereplaced in hermetically sealed jars and the lifetime of the animals wasrecorded. A control group of mice received no pre-treatment whilst othergroups received a prior intraperitoneal injection of 90 or 45 mg/kgCAPAH in one experiment, or 30 mg/kg of CAPAH in a second experiment(equivalent to about 1/10, 1/20 and 1/30 of the LD₅₀).

The results obtained, as shown in Table 7, indicate an extension oflifetime when using 90 or 45 mg/kg of CAPAH.

                  TABLE 7                                                         ______________________________________                                        Effect of CAPAH on lifetime following hypoxia induced by                      direct lack of oxygen                                                                        Lifetime (± deviation)                                      Treatment      minutes                                                        ______________________________________                                        Control        14.0                                                           90 mg/kg CAPAH 17.0 ± 0.1*                                                 45 mg/kg CAPAH 18.8 ± 1.1*                                                 Control        16.2 ± 0.6                                                  30 mg/kg CAPAH 16.4 ± 1.2                                                  ______________________________________                                         *indicates statistically significant difference from control             

(B)

White mice in groups of eight with a weight in the range of 18 to 21grams were injected subcutaneously with 300 mg/kg of aqueous sodiumnitrite and their subsequent lifetime was recorded. A control group ofmice received no additional pre-treatment but a second group received aprior intraperitoneal injection of 90 mg/kg CAPAH.

The results obtained, as shown in Table 8, indicate an extension oflifetime when using CAPAH.

                  TABLE 8                                                         ______________________________________                                        Effect of CAPAH on lifetime following hypoxia induced by                      sodium nitrite                                                                               Lifetime (± deviation)                                      Treatment      minutes                                                        ______________________________________                                        Control        13.5 ± 1.2                                                  90 mg/kg CAPAH 16.9 ± 1.0*                                                 ______________________________________                                         *indicates statistically significant difference from control             

We claim:
 1. A compound of formula (I): ##STR6## wherein each Xseparately is halogeno, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro or anunsubstituted or substituted amino group NRR' in which R and R' are eachseparately selected from hydrogen, C₁₋₄ alkyl groups and C₂₋₄halogenated alkyl groups;wherein Y is halogeno, hydroxy, C₁₋₄ alkoxy oran unsubstituted or substituted amino group NRR' in which R and R' areas defined above; wherein n represents 0, 1, 2 or 3 and n' represents 1,2, 3 or 4; wherein R¹ and R² each separately represent hydrogen,halogeno, phenyl or a C₁₋₄ alkyl group, or together represent a group═NOR" in which R" is hydrogen or is a group ZC(O)-- or (ZO)₂ P(O)--where Z is a C₁₋₄ alkyl group; and wherein R³ and R⁴ each separatelyrepresent hydrogen, acetyl, phenyl, 2,2,2-trichloro-1-hydroxyethyl or aC₁₋₄ alkyl group, or together represent a group ═CHR"' in which R"' is aC₁₋₄ alkyl, C₁₋₄ halogenated alkyl or phenyl group or represent a group═CH--CH═CHR"' in which R"' is as defined above, with any phenyl grouppresent in R³, R⁴ or R³ +R⁴ optionally being substituted by 1 to 3groups selected from halogeno, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitroand unsubstituted or substituted amino groups NRR' in which R and R' areas defined above; the compound optionally being in the form of aphysiologically acceptable salt.
 2. A compound according to claim 1, inwhich n is
 1. 3. A compound according to claim 2, in which X is NRR'. 4.A compound according to claim 3, in which NRR' is a dimethylamino groupsubstituted at the para position of the benzene ring with respect to thephosphorus-containing grouping.
 5. A compound according to claim 1, inwhich Y is a halogeno group.
 6. A compound according to claim 5, inwhich Y is chloro.
 7. A compound according to claim 1, in which n' is 2.8. A compound according to claim 1, in which R¹ and R² are eachhydrogen.
 9. A compound according to claim 1, in which R³ and R⁴ areeach hydrogen.
 10. A compound according to claim 1, in which R³ and R⁴are a group ═CHR"' or a group ═CH--CH═CHR"' where R"' is methyl, phenyl,nitrophenyl or hydroxyphenyl.
 11. A compound according to claim 1 being2-chloroethoxy(phenyl)phosphinylacetohydrazide or a physiologicallyacceptable salt thereof.
 12. A compound according to claim 1 being2-chloroethoxy-(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide or aphysiologically acceptable salt thereof.
 13. A compound according toclaim 1 being other than 2-chloroethoxy-(p-N,N-dimethylaminophenyl)phosphinylacetohydrazide or a physiologicallyacceptable salt thereof.
 14. A compound according to claim 1, which isin the form of a physiologically acceptable salt.
 15. A compoundaccording to claim 14 which is in the form of a hydrochloride salt. 16.A pharmaceutical composition comprising a compound according to claim 1together with a physiologically accceptable diluent or carrier.
 17. Apharmaceutical composition according to claim 16, in which thephysiologically acceptable diluent or carrier is a sterile and pyrogenfree liquid or a solid.
 18. A pharmaceutical composition according toclaim 16 which is formulated in unit dosage form.
 19. A method for thetreatment of a patient suffering from depression and/or in need ofmemory enhancement which comprises administering to said patient atherapeutically effective amount of a compound of formula (I) as definedin claim 1.